Stable tablets comprising simvastatin

ABSTRACT

A tablet comprising simvastatin and excipients, wherein the content of lactose, if any, is less than 75 percent of the total excipients by weight, and wherein the content of cellulose is more than 20 percent of the total excipients by weight.

BACKGROUND OF THE INVENTION

Simvastatin is a lipid-lowering agent that is produced syntheticallyfrom lovastatin. Simvastatin is disclosed and claimed in U.S. Pat. No.4,444,784. Tablets comprising simvastatin as the active ingredient aresold by Merck & Co., Inc. in the United States and elsewhere under thetradename Zocor™ in strengths of 5 mg, 10 mg, 20 mg, 40 mg and 80 mg.

With respect to pharmaceutical formulations (i.e. dosage forms)comprising simvastatin, the only information disclosed in U.S. Pat. No.4,444,784 is a statement that typical formulations for filling hardgelatin capsules comprise the active drug and finely divided lactose.

Zocor™ tablets are film-coated tablets, by which is meant that theyconsist of core tablets surrounded by a water-soluble film coating. Thelabelling for Zocor™ tablets indicate that the excipients (i.e. inactiveingredients) used in the core tablets are lactose, cellulose, starch,magnesium stearate, ascorbic acid, citric acid and butylatedhydroxyanisole (also known as BHA).

Lactose, cellulose, starch, and magnesium stearate are all very commonlyused as excipients in tablets. In particular, lactose and cellulose arevery commonly used as fillers and binders. When lactose is used as anexcipient, it is typically used in the largest quantity and typicallyconstitutes more than 75 percent of the total excipients by weight.Starch is very commonly used as a filler and disintegrant, and magnesiumstearate is very commonly used as a lubricant, to avoid sticking andbinding in the tabletting process.

The inclusion of BHA, ascorbic acid, and citric acid as excipients inthe core tablets is unusual, and the inclusion of these excipientsindicates that Merck & Co. Inc. found that it was necessary to includethese excipients to achieve satisfactory stability of the simvastatin inthe tablet. Simvastatin is prone to degradation due to oxidation of thediene and oxidation of the hydroxyl group in the simvastatin molecule.BHA and ascorbic acid are apparently included in the tablets asantioxidants. Citric acid is apparently added because it has chelationproperties with metal ions, which, in the absence of the citric acid,could catalyze the oxidation process.

The composition of the Zocor™ core tablets is thus relatively complex interms of the number of excipients used. Also, the use of BHA as anantioxidant usually requires the use of a solvent. That is to say, BHAis dissolved in a solvent, the solution is used to granulate thesimvastatin, optionally after mixing with one or more excipients, andthe wet mass is then dried to evaporate the solvent. The process ofmanufacture of the tablets is thus much more complex and expensive thana simple dry-mix process, by which is meant a process in which all ofthe ingredients are mixed together in dry form, and the mixture iscompressed into tablets, without adding a solvent and then drying toevaporate the solvent. It is clearly preferable to avoid the use ofsolvents, if possible, in order to simplify the process of manufacture.

Simvastatin is also a compound for which it is difficult to produce atablet formulation which exhibits rapid absorption after ingestion. Itis necessary that any tablet formulation that is developed as analternative to Zocor™ exhibit a rate of absorption on oraladministration that is equivalent to that of Zocor™.

In light of this prior art, the objective of the present invention is toenable the manufacture of simvastatin tablets so as to achieve at leastone or more, if not all, of the following:

-   -   1. Improved stability relative to tablets that use lactose as        the predominant excipient.    -   2. Rate and extent of absorption equivalent to Zocor™ upon oral        administration.    -   3. Elimination of the need to include citric acid as an        excipient.    -   4. Elimination of the need to include ascorbic acid as an        excipient.    -   5. Elimination of the need to include BHA as an excipient.    -   6. Production by a dry-mix method; i.e. without the need to        granulate with a solvent and then dry to evaporate the solvent.

BRIEF SUMMARY OF THE INVENTION

It has been found that rate of degradation of simvastatin issignificantly affected by the excipients with which it is mixed.

More particularly, it has been found that the stability of simvastatinin tablets is significantly improved by reducing or eliminating thelactose content, and by using cellulose, as a major excipient. Thetablets of the present invention thus comprise simvastatin andexcipients, wherein the content of lactose, if any, is less than 75percent of the total excipients by weight, and wherein the content ofcellulose is more than 20 percent of the total excipients by weight.

DETAILED DESCRIPTION OF THE INVENTION

Tablets comprising simvastatin will generally be made by mixingsimvastatin with excipients (inactive ingredients) and compressing themixture into tablets on a tablet press.

Among ingredients most commonly used as fillers and binders inpharmaceutical tablets are lactose (which may be either anhydrouslactose or lactose monohydrate) and cellulose. They are considered to bebinders as well as fillers, because they usually enable compression intohard tablets, if they are the predominant ingredients.

Because lactose is the predominant excipient used in Zocor™ tablets,which presumably were carefully developed to Merck & Co. Inc. formaximum stability, it has been surprising to discover that stability isbetter with cellulose than with lactose as principal excipient.

Tablets of the present invention will have a lactose content that isless than 75 percent, is preferably less than 60 percent, and is morepreferably less than 40 percent of the total excipient content byweight. Most preferably the tablets will be lactose free.

The tablets will comprise cellulose (which may be eithermicrocrystalline cellulose or powdered cellulose) as a filler andbinder. The amount of cellulose will exceed 20 percent, will preferablyexceed 40 percent, and will more preferably exceed 60 percent of thetotal excipients by weight.

Cellulose is often considered to be a disintegrant in addition to beinga filler and binder, because, like other disintegrants, it absorbs waterand swells, thus aiding in the disintegration of tablets containingcellulose when they are added to an aqueous medium. Nevertheless,tablets of the present invention will preferably also comprise adisintegrant other than cellulose.

Commonly used disintegrants include starch (which may bepregelatinized), croscarmellose sodium, carmellose calcium, sodiumstarch glycolate, and crospovidone. It has been further found thatstability of the simvastatin tablets is better when starch, sodiumstarch glycolate, or crospovidone is used as disintegrant, than wheneither croscarmellose sodium or carmellose calcium is used. Accordingly,the tablets of the present invention will preferably comprise starch,sodium starch glycolate or crospovidone, and will preferably notcomprise any croscarmellose sodium or carmellose calcium.

The presence of an adequate amount of a disintegrant other thancellulose is necessary to ensure that the tablets are bioequivalent toZocor™; that is to say that the rate of absorption of the simvastatin isequivalent to that of Zocor™ upon ingestion.

The United States Pharmacopoeia, 25^(th) edition, includes a dissolutiontest for simvastatin tablets. The test is done in apparatus 2 at 50 rpmin 900 mL of pH 7.0 buffer solution containing 0.5 percent dodecylsodium sulfate in 0.01M sodium phosphate. The specification requiresdissolution of not less than 75 percent in 30 minutes.

While tablets which comprise cellulose as the predominant excipient andwhich do not also comprise another disintegrant may exhibit rapiddisintegration in water and may even pass the United StatesPharmacopoeia dissolution test, such tablets will nevertheless beunlikely to be bioequivalent to Zocor™ tablets, as a result ofexhibiting slower dissolution than Zocor™ in gastric fluid, which has alower pH than used in the United States Pharmacopoeia test.

Where starch is used as the disintegrant, the quantity will preferablyexceed 12 percent and more preferably exceed 20 percent of the total ofexcipients by weight. Where the disintegrant is selected from sodiumstarch glycolate, crospovidone, croscarmellose sodium or carmellosecalcium (of which the first two of these are preferable as aforesaid forreasons of stability), the amount will preferably exceed 1 percent, morepreferably exceed 2 percent, and even more preferably exceed 3 percentof the total of excipients by weight.

The total of excipients selected from the group consisting of cellulose,starch, sodium starch glycolate will preferably exceed 65 percent, willmore preferably exceed 80 percent, will even more preferably exceed 90percent, and will most preferably exceed 95 percent of the total ofexcipients by weight.

It has been found that the stability of simvastatin in tablets is alsosignificantly affected by the choice of lubricant. Stability is improvedwhen magnesium stearate, which is by far the most commonly usedlubricant, is replaced by zinc stearate, or sodium stearyl fumarate.Thus tablets of this present invention will preferably be free ofmagnesium stearate, and will preferably comprise zinc stearate or sodiumstearyl fumarate.

By selecting excipients in accordance with the teaching of thisdisclosure, it is possible to significantly improve the stability ofsimvastatin so as to reduce or eliminate the need for the stabilizersthat are included in Zocor™ tablets.

Tablets of the present invention will thus optionally and preferably befree of citric acid. The tablets will also optionally and preferably befree of ascorbic acid. The tablets will preferably be free of bothcitric and ascorbic acid. The tablets will also optionally andpreferably be free of BHA. The tablets will preferably be free of allthree of citric acid, ascorbic acid and BHA.

As aforesaid, the inclusion of BHA in Zocor™ tablets requires the use ofa wet-granulation process in which the BHA is dissolved in solvent, thesolution is used to wet granulate the simvastatin (after it is mixedwith excipients), and the wet mass is then dried to evaporate thesolvent.

The tablets of the present invention will preferably be made by adry-mix process; that is to say, a process in which all of theingredients are mixed together in dry form, without any step of addingsolvent and then drying to evaporate the solvent.

The invention will be better understood from the following examples,which are meant to be illustrative, and not limiting of the scope of theinvention.

EXAMPLES 1 TO 7

Example No. 1 2 3 4 5 6 7 Simvastatin 5.0 5.0 5.0 5.0 5.0 5.0 5.0Anhydrous Lactose 39.6 25.0 25.0 25.0 25.0 25.0 25.0 Microcrystalline 014.6 0 0 0 0 0 Cellulose Starch, Pregelatinized 0 0 14.6 0 0 0 0Croscarmellose 0 0 0 14.6 0 0 0 Sodium Carmellose Calcium 0 0 0 0 14.6 00 Sodium Starch 0 0 0 0 0 14.6 0 Glycolate Crospovidone 0 0 0 0 0 0 14.6Magnesium Stearate 0.4 0.4 0.4 0.4 0.4 0.4 0.4 45.0 45.0 45.0 45.0 45.045.0 45.0

For each of examples 1 to 7, the ingredients were mixed in theproportions shown, and the powder mixture was then compressed intotablets of unit weight 45 mg, so that each tablet comprised about 5 mgof simvastatin. In the tablets of example 1, the only excipients arelactose as filler-binder, and magnesium stearate as lubricant. In eachof examples 2 to 7, 14.6 mg of the lactose is replaced by 14.6 mg of oneof cellulose, starch, croscarmellose sodium, carmellose calcium, sodiumstarch glycolate and crospovidone.

Tablets of each of examples 1 to 7 were stored at 60° C. for four weeksand then tested for the amount of simvastatin-oxolactone, which is theproduct of oxidation of the hydroxyl group in the simvastatin molecule.The testing was done by an HPLC (high performance liquidchromatographic) method, with results as follows, as a percentage of thesimvastatin content: Example No. 1 2 3 4 5 6 7 % Oxolactone .108% .104%.154% .169% .187% .142% .118%

The initial level of oxolactone in the simvastatin used to make thetablets was about 0.04%.

Comparing the results for examples 1 and 2 indicates that replacing partof the lactose by cellulose reduced the rate of oxidation.

Comparing the results of examples 3 to 7 with the result of example 1indicates that the addition of any of the five disintegrants increasesthe rate of oxidation (at least when lactose is still the primaryexcipient), but that the rate of oxidation is lower when thedisintegrant is crospovidone, sodium starch glycolate, or starch, thanwhen it is croscarmellose sodium or carmellose calcium.

EXAMPLES 8 TO 13

Example No.: 8 9 10 11 12 13 Simvastatin 5.0 5.0 5.0 5.0 5.0 5.0Microcrystalline Cellulose 39.9 25.3 25.3 25.3 25.3 25.3 Starch,Pregelatanized 0 14.6 0 0 0 0 Croscarmellose Sodium 0 0 14.6 0 0 0Carmellose Calcium 0 0 0 14.6 0 0 Sodium Starch Glycolate 0 0 0 0 14.6 0Crospovidone 0 0 0 0 0 14.6 Magnesium Stearate 0.1 0.1 0.1 0.1 0.1 0.145.0 45.0 45.0 45.0 45.0 45.0

Examples 8 to 13 are repeats of examples 2 to 7, with all of the lactosereplaced by cellulose, and the amount of magnesium stearate per tabletreduced from 0.4 mg to 0.1 mg. The tablets were made by the same processas used in examples 1 to 7.

Sample tablets were also stored at 60° C. for 4 weeks and tested by thesame method, with results as follows: Example No. 8. 9 10 11 12 13 %Oxolactone .098% .113% .129% .143% .101% .095%

Comparing the result for example 8 to the results for examples 1 and 2confirms that the rate of oxidation is further reduced by replacing thebalance of the lactose with more cellulose. Comparing the results ofexamples 9 to 13 again confirms that the rate of oxidation is lower whenthe disintegrant is one of crospovidone, sodium starch glycolate orstarch, than when it is croscarmellose sodium or carmellose calcium.

EXAMPLES 14 AND 15

Example No. 14 15 Simvastatin 5.0 5.0 Crospovidone 34.9 34.9 MagnesiumStearate 0.1 0 Zinc Stearate 0 0.1 40.0 40.0

Tablets of examples 14 and 15 were made by the same process as examples1 to 13, except that the tablets were made at a unit weight of 40 mginstead of 45 mg. The purpose of examples 14 and 15 was to compare theeffect on oxidation rate when magnesium stearate is replaced by zincstearate as lubricant.

Again tablets were stored at 60° C., and after 4 weeks samples weretested with results as follows: Example No. 14 15 % Oxolactone 0.193%0.146%

These results confirm that the oxidation rate is reduced by eliminatingmagnesium stearate as lubricant, and replacing it by zinc stearate.Comparing the results of examples 14 and 13, also shows that theoxidation rate is lower when the excipient content is mostly cellulosethan when it is mostly crospovidone.

EXAMPLES 16 TO 21

Example No. 16 17 18 19 20 21 Simvastatin 5.0 5.0 5.0 5.0 5.0 5.0Microcrystalline Cellulose 39.9 30.0 39.9 30.0 40.0 30.0 Crospovidone 09.9 0 9.9 0 10.0 Zinc Stearate 0.1 0.1 0 0 0 0 Sodium Stearyl Fumarate 00 0.1 0.1 0 0 45.0 45.0 45.0 45.0 45.0 45.0

Tablets of examples 16 to 21 were made by the same process as examples 1to 13. The purpose of these examples was to compare the stability oftablets with zinc stearate as lubricant, sodium stearyl fumarate aslubricant, and no lubricant at all, all both with and withoutcrospovidone as disintegrant.

Tablets for each of examples 16 to 21 were stored at 60° C. for 2 weeks,and then tested with results as follows: Example No. 16 17 18 19 20 21 %Oxolactone .055% .055% .046% .051% .046% .041%

These results indicate good stability, regardless of whether the tabletscontain sodium stearyl fumarate or zinc stearate as lubricant, or nolubricant at all.

1. A pharmaceutical tablet which comprises simvastatin and excipients,wherein the amount of lactose, if any, is less than 75 percent of thetotal of excipients by weight, and wherein the amount of cellulose ismore than 20 percent of the total excipients by weight.
 2. The tablet ofclaim 1 wherein the amount of lactose is less than 60 percent of thetotal of excipients by weight.
 3. The tablet of claim 1 wherein theamount of lactose is less than 40 percent of the total of excipients byweight.
 4. The tablet of claim 1 that is lactose free.
 5. The tablet ofany of claim 1 wherein the amount of cellulose is more than 40 percentof the total of excipients by weight.
 6. The tablet of claim 1 whereinthe amount of cellulose is more than 60 percent of the total ofexcipients by weight.
 7. The tablet of claim 1 that comprises as adisintegrant other than cellulose.
 8. The tablet of claim 7 wherein thedisintegrant is starch.
 9. The tablet of claim 8 wherein the amount ofstarch exceeds 12 percent of the total of excipients by weight.
 10. Thetablet of claim 8 wherein the amount of starch exceeds 20 percent of thetotal of excipients by weight.
 11. The tablet of claim 7 wherein thedisintegrant is crospovidone.
 12. The tablet of claim 7 wherein thedisintegrant is sodium starch glycolate.
 13. The tablet of claim 7wherein the disintegrant is either croscarmellose sodium or carmellosecalcium.
 14. The tablet of any one of claims 11 to 13 wherein the amountof the disintegrant exceeds 1 percent of the total of excipients byweight.
 15. The tablet of any one of claims 1 1 to 13 wherein the amountof the disintegrant exceeds 2 percent of the total of excipients byweight.
 16. The tablet of any one of claims 11 to 13 wherein the amountof the disintegrant exceeds 3 percent of the total of excipients byweight.
 17. The tablet of claim 1 wherein excipients selected from thegroup consisting of cellulose, starch, sodium starch glycolate, andcrospovidone exceed 65 percent of the total excipients by weight. 18.The tablet of claim 1 wherein excipients selected from the groupconsisting of cellulose, starch, sodium starch glycolate, andcrospovidone exceed 80 percent of the total excipients by weight. 19.The tablet of claim 1 wherein excipients selected from the groupconsisting of cellulose, starch, sodium starch glycolate, andcrospovidone exceed 90 percent of the total excipients by weight. 20.The tablet of claim 1 wherein excipients selected from the groupconsisting of cellulose, starch, sodium starch glycolate, andcrospovidone exceed 95 percent of the total excipients by weight. 21.The tablet of claim 1 that is free of magnesium stearate.
 22. The tabletof claim 1 that comprises zinc stearate.
 23. The tablet of claim 1 thatcomprises sodium stearyl fumarate.
 24. The tablet of claim 1 that isfree of citric acid.
 25. The tablet of claim 1 that is free of ascorbicacid.
 26. The tablet of claim 1 that is free of butylatedhydroxyanisole.
 27. The tablet of claim 1 when made by a dry-mixprocess.